elementary, my dear watson, the clue is in the genesor is it?

SPECIAL LECTUREto mark the centenary of the British Psychological Society

Elementary, my dear Watson,the clue is in the genes . . . or is it?

ANNETTE KARMILOFF-SMITHFellow of the Academy

Introduction

THE SEEMINGLY LIGHT-HEARTED, yet in fact serious, title of my lecturerequires some explanation. This lecture celebrated the Centenary of theBritish Psychological Society, hosted by the British Academy (whosecentenary is but one year later). The British Academy covers both theHumanities (Archaeology, Modern Languages, Literature, History,Theology, Philosophy, etc.) and the Social Sciences (Law, Economics,Social Anthropology, Geography, Sociology, Politics, Psychology, etc.).Even the Psychology Section of the Academy covers a wide range of dis-ciplines: social psychology, cognitive psychology, adult neuropsychology,health psychology, emotional psychology, primate cognition, etc. And myown speciality—developmental cognitive neuroscience—is probably oneof the furthest from the Humanities. So the problem the lecture posedwas to link my interest in genotype/phenotype relations with the interestsof these other disciplines, and the name ‘Watson’ came to mind. On thescience side: James Watson contributed to the discovery of the structureof DNA in the 1950s and, half a century later, to the sequencing of thehuman genome. On the humanities side: although Arthur Conan Doyleis hardly one of Britain’s greatest literary figures, the sidekick of hisfamous character, Sherlock Holmes, is also called Watson. In fact, the

Proceedings of the British Academy, 117, 525–543. © The British Academy 2001.

Read at the Academy 5 November 2001.

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Watson link turns out to be less tenuous than it might seem, becauseunderstanding the complex pathways from gene-to-brain-to-cognitiveprocesses-to-behaviour is not unlike a detective story, in which seeminglyunimportant clues very early in development play a vital role in the finaloutcome.

As we learn more about genes, there is a temptation, not only in thepress but even in some of the psychological, linguistic and philosophicalliterature, to seek one-to-one relationships between specific genes (or spe-cific sets of genes) and complex higher-level behaviours like altruism,aggression, intelligence, spatial cognition, or language. In a series of pop-ular books, Steven Pinker has repeatedly supported such assumptions byusing data from neuropathology (Pinker, 1994, 1997, 1999; see alsoTemple, 1997). Many theorists of a nativist persuasion claim that humaninfants are born with genetically programmed brains that contain spe-cialised components, not only for low-level perceptual processes, but alsofor higher-level cognitive modules like language, mathematics, spatialcognition, face processing, and the like. A direct link is then soughtbetween these specialised modules and specific genes. In other words, theinfant brain is claimed to be like a Swiss Army knife, with the notion thatevolution has created increasingly complex, uniquely specialised genes(Cosmides & Tooby, 1994). Data used to bolster such claims come fromadult neuropsychological patients and from children with genetic dis-orders. But are these two sources of data as straightforward as they seem?It is indeed the case that adults who suffer stroke or accident can damagea specific part of the brain that may then result in an isolated impairment.For instance, patients with prosopagnosia have normal language, are ableto recognise different categories of objects, yet present with an isolatedimpairment in recognising faces. Other adult patients may process faceswell, use a wide variety of words, but present with difficulties puttingwords together into grammatical form, and so forth. However, it is vitalto recall that these selective deficits in neuropsychological patients comefrom adult patients who had previously developed normally throughouttheir lives until their brain insult. Their brains had by adulthood alreadybecome specialised and subsequently damaged. But their brains were notdamaged in early childhood. Thus, one cannot simply assume that theinfant start-state is organised in the same way as the adult end-state.Brains develop dynamically, not as a series of juxtaposed, isolated parts.Therefore, it could well be that the specialisations for face processing, lan-guage and the like in adults are the result of a developmental process, notits starting point (Karmiloff-Smith, 1992, 1998; Paterson et al., 1999).

526 Annette Karmiloff-Smith


Thus, isolated impairments in adulthood may tell us relatively little aboutthe infant brain and its relationship with gene expression.

While adult neuropsychology patients may therefore be uninformativeabout innateness, there are a number of genetic disorders that at firstblush seem to fit the nativist model. Dyslexia is a disorder with a cleargenetic component. The syndrome appears to present with impairmentssolely in reading. A similar case holds for Specific Language Impairment,SLI, which by its very name suggests that language alone is impaired,with the rest of the child’s skills argued to be intact. Williams syndrome,discussed in more detail below, has been hailed by many, including Pinker(1994, 1997, 1999), as the prime example of impaired and intact cognitivemodules directly linked to mutated and intact genes. Indeed, in compar-ing SLI and Williams syndrome, Pinker argues for a clear-cut dissociationbetween the two disorders at both the genetic and cognitive levels,appealing to the logic of adult neuropsychology:

Overall, the genetic double dissociation is striking, suggesting that language isboth a specialisation of the brain and that it depends on generative rules thatare visible in the ability to compute regular forms. The genes of one group ofchildren [SLI] impair their grammar while sparing their intelligence; the genesof another group of children [WS] impair their intelligence while sparing theirgrammar. (1999, p. 262)

By contrast, in the lecture I challenge such assumptions and argue thatthere is no one-to-one, direct mapping between specific sets of genes andcognitive-level outcomes. Rather, there are very indirect mappings, withthe regulation of gene expression more likely to contribute to very broaddifferences in developmental timing, neuronal type, neuronal density, fir-ing thresholds, neurotransmitter types, etc. In the Neuroconstructivistframework for which I argue, gene/gene interaction, gene/environmentinteraction and, crucially, the process of ontogeny itself (pre- and post-natal development) are all considered to play a vital role in how genes areexpressed and how the brain progressively sculpts itself, slowly becomingspecialised over developmental time. The infant brain is not simply aminiature version of the adult brain.

The neuroconstructivist framework

A genetic disorder, Williams syndrome (WS), serves as an example of theNeuroconstructivist approach to genotype/phenotype relations. A greatdeal is known about both the WS genotype and the WS phenotype (the

THE CLUE IS IN THE GENES . . . OR IS IT? 527


physical and behavioural outcome). Yet despite this, the relationshipbetween genotype and phenotype is far from obvious. WS occurs inapproximately 1 in 25,000 live births and involves the deletion of some 17genes on the long arm of one copy of chromosome 7q11,23 (Donnai &Karmiloff-Smith, 2000). People with WS present with atypical brainanatomy (Jernigan et al., 1993) and atypical brain chemistry (Rae et al.,1999). Their brains are about 20 per cent smaller in volume than normalbrains, with abnormal size, orientation and density of neurons, and atyp-ical proportional volumes of several brain regions. Structural abnormal-ities of genetic origin are likely to be subtle and diffuse, not like adultneuropsychological patients, and this seems to hold for WS. Such subtlebut widespread abnormalities give rise to atypical patterns of interactionsbetween different brain regions. The WS brain is not a normal brain withparts intact and parts impaired.

People with WS present with a facial dysmorphology, as can be seenin Figure 1, as well as cardiac and renal abnormalities. Their IQs are inthe 50–65 range, with an uneven cognitive profile in which languagescores usually outstrip scores on spatial tasks.

The difference in WS between the very impaired spatial skills and theseemingly proficient face processing skills is particularly striking. Partici-pants are given the Benton Face Processing Task (Benton et al., 1983)which requires them to select from six faces, shown in different orienta-tions, the three that are identical to a model face. On this task, childrenand adults with WS tend to score in the normal range, indicating a par-ticular proficiency with face identity matching in this clinical population(Bellugi et al., 1988; Bellugi, Wang & Jernigan, 1994; Karmiloff-Smith,1997). This peak of ability is also evident using the Rivermead FaceProcessing Task (Wilson, Cockburn, & Baddeley, 1990), one in whichpatients have to recall which faces they have already seen presentedamongst other, new faces. Here, too, patients with WS perform well(Udwin & Yule, 1991). In sum, children and adults with WS are especiallyproficient at recognising and remembering faces. In stark contrast to thisstands their serious impairment when asked to match the orientation ofone line amongst a choice of others on the Benton Line Orientation Task(Benton et al., 1983). Here, people with WS score at floor, and this seriousdeficit continues throughout adulthood (Bellugi et al., 1988; Rossen et al.,1996).

The clear-cut disparity between face and space processing in Williamssyndrome led a number of psychologists of a nativist persuasion to claimthat the syndrome presents with an intact face processing module and an



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impaired space processing module (Bellugi et al., 1994). Geneticists work-ing on the identification of the functions of the genes in the deleted WSregion used these psychological data to make specific claims aboutgenotype–phenotype relations (Frangiskakis et al., 1996). The geneticistsdiscovered one family some members of which had a deletion of twogenes (Elastin and Limkinase1) in the same region of chromosome 7 aspeople with WS. Since the Limkinase1 gene (LIMK1) is expressed in thebrain, and since those members of this family with the genetic mutationdisplayed some spatial deficits, the geneticists leapt to the conclusion thathaploinsufficiency (one copy only) of LIMK1 was directly linked to thespatial impairment seen in WS (Frangiskakis et al., 1996). It took littletime for the press to hail these findings in terms of the discovery of ‘agene for spatial cognition’ or even ‘a gene for intelligence’.

There are, however, several problems with the direct mapping of theLIMK1 gene to spatial cognition. Firstly, to reiterate, direct one-to-onemappings between specific genes and specific higher-level cognitive out-comes like spatial cognition are highly unlikely. Genotype–phenotyperelationships are exceedingly indirect. Moreover, it is one thing to statethat a mutated gene contributes to the disruption of a cognitive outcome,but quite another to claim that this is the ‘gene for’ that outcome. Sec-ondly, drawing such strong conclusions from the study of a single familywho may have other genetic impairments is premature. Thirdly, using theadult outcome to draw such genotype/phenotype conclusions negates therole of ontogenetic development in gene expression.

My team and I thus decided that three approaches were required toexplore the genotype/phenotype relationship in WS: (i) together with col-leagues in Clinical Genetics at St Mary’s Hospital, Manchester, we stud-ied a larger number of patients with partial gene deletions in the WScritical region; (ii) we carried out in-depth studies of those domains whichother research teams had deemed to be intact in WS (face processing, lan-guage and social cognition), by dissecting the phenotype in detail; and,(iii) we explored the phenotypic start-state by studying infants with WSand comparing them to the phenotypic end-state in adults with WS aswell as to infants with other genetic disorders. It is the second and thirdapproaches that particularly illustrate the Neuroconstructivist frame-work, but first we will turn to the studies of patients with partial deletionsin the WS critical region who do not have Williams syndrome.



Studies of the relationship between genotype and phenotype in Williamssyndrome

Our studies of patients with partial deletions in the WS critical region onchromosome 7 have thus far covered four patients who have been exam-ined in detail (Tassabehji et al., 1999; Karmiloff-Smith et al., 2002). Twobrothers in their thirties presented with a deletion of 80kb which includedthe two genes (Elastin and LIMK1) on which the claims of Frangiskakis etal. (1996) were made. Although the brothers had similar heart problems topeople with WS (supravalvular aortic stenosis, SVAS), they did not have adysmorphic face, nor did they show any imbalance between language andspatial cognition or between the latter and face processing. Their IQs werein the normal range. The third patient, in his late twenties, had a slightlylarger deletion, around 100 kb, including ELN, LIMK1 and the WBSCR1gene. He, too, had the SVAS heart abnormality, but no facial dysmor-phology. He was a student of engineering at Athens University, with IQin the normal range. The fourth patient, an 8-year-old girl, had a muchlarger deletion, stretching some 800 kb along the WS critical region, with13 of the 17 genes deleted, including, ELN and LIMK1. Despite this hugedeletion and very serious heart problems, the young girl was well abovenormal intelligence in all domains and displayed no imbalances whatso-ever in her cognitive profile. Figures 2 and 3 illustrate how our patientsdiffered from even our highest functioning woman with WS. Note thateven when one of our SVAS patients was at the lower end of the normalrange of intelligence and could be matched in terms of overall cognitiveability with our high-functioning WS patient (Fig. 2), the pattern of


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Figure 2. WS/SVAS individual patients’ General Cognitive Ability (GCA).


language versus spatial abilities differed radically between all the SVASpatients and the one with WS (Fig. 3). The difference between the profilesis striking, with the WS patient showing the pattern typical of this clinicalgroup. Our results make it clear that deletion of LIMK1, a mutationcharacteristic of all our SVAS and WS patients, cannot alone explain theparticularly serious spatial deficits in WS. The in-depth study thusdemonstrated that the direct one-to-one genotype/phenotype relationbetween LIMK1 and spatial impairments claimed by previous research-ers was erroneous and cannot alone explain the atypical developmentalpathway seen in Williams syndrome.

In-depth studies of behavioural proficiency in Williams syndrome

Our second approach was to undertake in-depth studies of the ostensiblyproficient domains of face processing, language, and social cognition inolder children and adults with Williams syndrome. These were of particu-lar interest for two reasons. First, the literature is replete with claims thatthese domains represent intact modules in Williams syndrome (Bellugi,Wang & Jernigan, 1994; Pinker, 1994, 1997, 1999; Rossen et al., 1996). Yetour neuroconstructivist approach regarding the dynamics of overall braindevelopment suggests that we should find subtle deficits even in proficientdomains. Second, it is none the less unquestionable that people withWilliams syndrome show far greater proficiency in these domains com-pared to their seriously impaired spatial cognition. Such strikingly unevencognitive profiles are unusual in developmental disorders and are thusworthy of further study.


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Figure 3. WS/SVAS individual patients’ verbal/spatial abilities (excluding non-verbalreasoning).


Face processing is, as mentioned above, a domain in which peoplewith WS seem to excel. However, do behavioural scores ‘in the normalrange’ necessarily entail normal cognitive processes and normal geneexpression? We set out to examine this question in a series of behaviouraland brain imaging studies. We first replicated the findings that, on theBenton Face Processing Task, people with WS score surprisingly well(Karmiloff-Smith, 1997). We then tested our WS group on other, moredetailed face processing tasks. For example, participants were asked tomatch faces in terms of their emotional state, lip reading, eye gaze direc-tion and identity. We also varied whether stimuli were presented full faceor three-quarters, whether the eyes were covered or the hairline masked(Bruce et al., 2000). At first blush, the WS group seemed to perform well.However, once we examined separately those items which could be solvedby looking simply at one of the features of a face (the eyes, the cheekbone, the shape of the ears, etc.) and those for which the whole configu-ration of the face had to be taken into account, a striking differenceappeared in the WS data. For featural processing the WS group per-formed like normal controls. However, their scores were at chance whenthey had to analyse the face configurally (Karmiloff-Smith, 1997). Heretheir data were very different from the controls who processed the facesconfigurally, i.e., the controls looked at the whole face and the relation-ships between the parts. People with Williams syndrome processed thefaces featurally: they focused on single details in each face and performedpoorly when they needed to rely on configural information (see Fig. 4).They also do not show the typical inversion effect that normal controlsdisplay when faces are presented upside down (Deruelle et al., 1999). In


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Figure 4. Featural and configural processing in WS and controls.


other words, WS patients perform equally well on upright and invertedfaces, whereas controls are significantly worse on inverted faces. This isbecause normal controls use two different processes—configural forupright faces, featural for inverted faces—whereas the WS group use fea-tural processing whichever way the face stimuli are presented. So the WSbehavioural scores ‘in the normal range’ on standardised face processingtasks like the Benton and the Rivermead must be arrived at via a differentcognitive process compared to normal controls.

Such differences between normal controls and WS patients also holdfor our studies of the functioning of WS brains. Over the past decade,powerful new tools for imaging the workings of the brain have becomeincreasingly available. Some of these methods are based on measures ofblood oxygenation and flow (Positron Emission Tomography (PET),functional Magnetic Resonance Imaging (fMRI)), while others detect themagnetic or electrical fields generated when groups of neurons fire syn-chronously within the brain (Magneto-encephalography (MEG), EventRelated Potentials (ERP)). In general, methods related to blood flow arethought to have better spatial resolution (of the order of millimetres),whereas the other methods have better temporal resolution (of the orderof milliseconds). With the advent of event-related fMRI and High-Density ERP, both types of method are now working towards better spa-tial and temporal resolution within a single approach. We decided to useHD-ERP because this is easy to administer, is totally non-invasive andour patients enjoy participating (see Fig. 5). While normal controlsprocess faces predominantly within the right hemisphere, people with WSshow bilateral or predominantly left hemisphere processing (Mills et al.,2000). Furthermore, normal controls differ in brain electrophysiologywhen processing human faces, monkey faces or cars, whereas our researchshowed that people with WS process all three in the same way (Grice etal., 2001). Contrary to claims in the literature, it is clear that people withWS do not have an intact, specialised face processing module. Thus, it isnot the case that face processing is intact and spatial processing isimpaired: both follow atypical pathways in WS, compared to controls,once experimental design delves beneath the surface of behaviouralscores.

Our other cognitive-level studies reveal the same subtle impairmentswith respect to language and social cognition (Böhning, Campbell, &Karmiloff-Smith, 2002; Grant et al., 1996, 1997; Grant, Valian &Karmiloff-Smith, 2002; Karmiloff-Smith et al., 1995, 1997, 1998; Lainget al., 2001, 2002; Stevens & Karmiloff-Smith, 1997; Thomas et al., 2001;



Tyler et al., 1997). These are two further domains which some researchersargue to be intact in WS. Yet, in-depth studies of children and adults withWS reveal serious delays as well as numerous deficits in both languageand social cognition (see, also, Jarrold, Baddeley & Hewes, 1998; Mervis,Bertrand, & Robinson, 1999; Tager-Flusberg & Sullivan, 2000; Vicari etal., 1996). Recall, however, that nativist claims, and the use of a geneticdisorder like Williams syndrome to support those claims, require a pattern


Figure 5. WS adolescent in HD-ERP geodesic net.


of intact versus impaired modules formed from intact versus mutatedgenes, as the earlier citation from Pinker illustrates. Differentiatingbetween superficial behavioural scores and underlying cognitive processesreveals that this is not the case.

Comparing the infant start state with the adult phenotypic outcome

Our third line of experimental attack was to explore whether the patternof deficits and proficiencies found in adults is the same in infants withWilliams syndrome. In other words, can one simply assume that theuneven profile in the outcome will have been identical in the start state ininfancy? We tested this assumption in the domains of face processing,language, social cognition, and number, and also examined whether thetypical language/spatial cognition imbalance in adulthood was alreadyapparent in very young children. In each domain, we endeavoured to keepthe experimental stimuli the same for very young children as those that wehad used in our adult studies. Obviously the actual methodologies had tobe adapted to the age of the infants and toddlers, and for this we usedeither the preferential looking technique (Fig. 6) or the head-turntechnique (Fig. 7).

In order to assess their face processing abilities, infants and toddlerswere shown a series of schematic faces. Some of these were identical toone another whereas others had been modified either in terms of features(round eyes were changed to triangular or square eyes) or of configur-ation (a face was stretched or squashed so that the distance between fea-tures was altered). Our results suggest that infants with WS notice bothfeatural and configural changes in faces, but, unlike control infants, theyprefer to focus on features if given a choice between the two (Humphreys,Ewing & Karmiloff-Smith, 2002). Using the same stimuli, we had earlierfound that adults with WS are significantly less accurate (see Fig. 8) andtake significantly longer (see Fig. 9) to notice configural changes com-pared to normal control adults (Humphreys & Karmiloff-Smith, 2000).So, the tendency in adulthood to focus on features seems to be a functionof an early developmental tendency in Williams syndrome.

To test whether children with WS notice differences in number, infantswere shown on two monitors (see Fig. 6) pairs of pictures of two objectsand then, after familiarisation, one image suddenly displayed threeobjects. Normal controls always look longer at the display containing thealtered number. This turned out also to be true of infants with WS. Theynoticed small changes in numerosity, whereas infants with Down’s syn-



drome (DS) of the same chronological and mental age did not (Patersonet al., 1999). Yet in adulthood, the opposite pattern obtains: people withDS turn out to be less impaired in arithmetic tasks than those with WS(Paterson et al., 2002). So the pattern in the WS infant start-state isdifferent from the adult phenotypic outcome in the number domain.

Finally, we tested infants with Williams syndrome and Down’s syn-drome with respect to their early language comprehension. Here, theresults were very different. The infants with WS turned out to be just asseriously delayed as those with DS and significantly worse than bothmental age-matched and chronological age-matched controls (Paterson,et al., 1999). This stands in sharp contrast to adulthood when it is thosewith WS who clearly outstrip adults with DS in the language domain.Thus, once again, the pattern in the adult outcome cannot be used simplyto assume what the infant start-state is like or to make claims about geneexpression. The process of development modifies such patterns.


Figure 6. Preferential looking technique.


Our studies of infants and toddlers in the domains of face processing,number, and language clearly show a very different cognitive profile ininfancy compared to adulthood (Paterson et al., 1999; see, also, Laing etal., 2002 for studies of infant and toddler social cognition in Williamssyndrome). Yet, nativist arguments using adult profiles from genetic dis-orders to make claims about impaired and intact innate modules wouldrequire that the infant profiles look similar to the phenotypic outcome,but they do not.

Finally, we examined a number of low-level mechanisms in Williamssyndrome, with the hypothesis that subtle impairments early on in devel-opment impact over time on the final outcome. We were able to identifyatypical eye movement planning in infants with WS (Brown et al., 2002)and atypical sychronisation of oscillatory brain activity in adolescentsand adults with WS (Grice et al., 2001). These basic impairments affectfundamental processes that have a cascading impact on developmentfrom early infancy onwards.


Figure 7. Head-turn preference technique.



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Figure 8. Accuracy of featural versus configural processing.

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Figure 9. Speed taken to notice featural versus configural changes.


At present, my team is carrying out the same exercise with othergenetic disorders, such as Velocardiofacial syndrome (another microdele-tion disorder like Williams syndrome, but on chromosome 22), Down’ssyndrome, autism and Fragile X syndrome. We dissect the cognitive pro-file at both the behavioural and brain levels, and trace development backto its origins in infancy. Yet, even in a syndrome with a single mutatedgene, like Fragile X syndrome, the same story holds: we are discoveringsubtle deficits across numerous aspects of the developing system. So, irre-spective of whether one focuses on multiple or single gene disorders ofgenetic origin, direct relations between specific genes and cognitive-leveloutcomes turn out to be highly unlikely.

Concluding comments

In this lecture I argued against the assumption that children with geneticdisorders present with brains like adult neuropsychological patients, i.e.,a pattern of intact and impaired cognitive modules. The adult neuropsy-chological model is a static one of the structure of the human brain,because it focuses on adults whose brains are already fully formed. Butpre- post-natal brain development is a dynamic process which involvesinteractions across the whole brain. The range of findings from our stud-ies of infants, children, adolescents and adults with Williams and othersyndromes suggests that it cannot be taken for granted that the infantstart state is necessarily the same as the phenotypic outcome. Thus, claimsabout innate modules and how they relate to mutated and intact genesmust be constrained by knowledge of the profile of abilities and impair-ments found in early childhood as well as the subsequent developmentaltrajectory over time. Furthermore, neuropsychological cases (normaladults who suffer a brain insult) also cannot be used to make claims aboutevolution and the ontogenetic start state, because the structure of the nor-mal adult brain is the end product of a non-static process over develop-mental time. Thus, both these sources of data need to be treated withextreme caution if used to bolster claims about genetically programmed,modular specialisations of the human brain. The contrasting view pre-sented in this lecture is that our aim should be to understand how genesare expressed through development, because the major clue to geno-type–phenotype relations is not simply in the genes, or simply in the inter-action between genes and environment, but in the very process ofdevelopment itself.



References

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—— Wang, P. P., & Jernigan, T. L. (1994), ‘Williams Syndrome: An unusual neu-ropsychological profile’, in S. H. Broman & J. Grafman (eds.), Atypical CognitiveDeficits in Developmental Disorders. (Hillside, NJ).

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Böhning, M., Campbell, R., & Karmiloff-Smith, A. (2002), ‘Audiovisual Speech Per-ception in Williams Syndrome’, Neuropsychologia, 40/8: 1396–1406.

Brown, J., Johnson, M. H., Paterson, S., Gilmore, R., Gsödl, M., Longhi, E., &Karmiloff-Smith, A. (2002), ‘Spatial representations for action in infants withWilliams Syndrome: Do they have a specific dorsal pathway deficit?’ (submitted).

Bruce, V., Campbell, R., McAuley, S., Doherty-Sneddon, G., Langton, S., Import, A.,& Wright, R. (2000), ‘Testing face processing skills in children’, British Journal ofDevelopmental Psychology, 18: 319–33.

Cosmides, L., & Tooby, J. (1994), ‘Origins of domain specificity: The evolution offunctional organization’, in L. Hirschfeld and S. Gelman (eds.), Mapping theMind. (Cambridge).

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Donnai, D., & Karmiloff-Smith, A. (2000), ‘Williams syndrome: From genotypethrough to the cognitive phenotype’, American Journal of Medical Genetics: Sem-inars in Medical Genetics, 97 (2): 164–71.

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Grant, J., Valian, V., & Karmiloff-Smith, A. (2002), ‘A study of relative clauses inWilliams syndrome’, Journal of Child Language, 29: 403–16.

—— Karmiloff-Smith, A., Berthoud, I., & Christophe, A. (1996), ‘Is the language ofpeople with Williams syndrome mere mimicry? Verbal short-term memory in aforeign language’, Cahiers de Psychologie Cognitive, 15: 615–28.

—— —— Gathercole, S., Paterson, S., Howlin, P., Davies, M., & Udwin, O. (1997),‘Verbal Short-term Memory and its relation to Language Acquisition in WilliamsSyndrome’, Cognitive Neuropsychiatry, 2/2: 81–99.

Grice, S., Spratling, M. W., Karmiloff-Smith, A., Halit, H., Csibra, G., de Haan, M.,& Johnson, M. H. (2001), ‘Disordered visual processing and oscillatory brainactivity in autism and Williams Syndrome’, NeuroReport, 12: 2697–700.

Humphreys, K. J., & Karmiloff-Smith, A. (2000), ‘Local and configural processing inadults with Williams Syndrome’, Cognitive Neuroscience, Sept. 2000.

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Williams Syndrome: Infant Precursors in Developmental Disorders’. To be pre-sented at the International Conference on Infant Studies, Toronto.

Jarrold, C., Baddeley, A. D., & Hewes, A. K. (1998), ‘Verbal and nonverbal abilitiesin the Williams syndrome phenotype: Evidence for diverging developmentaltrajectories’, Journal of Child Psychology and Psychiatry, 39: 511–23.

Jernigan, T. L., Bellugi, U., Sowell, E., Doherty, S., & Hesselink, J. R. (1993), ‘Cere-bral morphologic distinctions between Williams and Down syndromes’, Archives-of-Neurology, 50(2): 186–91.

Karmiloff-Smith, A. (1992), Beyond Modularity: A Developmental Perspective on Cog-nitive Science (Cambridge).

—— (1997), ‘Crucial differences between developmental cognitive neuroscience andadult neuropsychology’, Developmental Neuropsychology, 13/4: 513–24.

—— (1998), ‘Development itself is the key to understanding developmental disor-ders’, Trends in Cognitive Sciences, 2: 389–98.

—— Grant, J., Berthoud, I., Davies, M., Howlin, P., & Udwin, O. (1997), ‘Languageand Williams Syndrome: How Intact is “Intact”?’ Child Development, 68/2: 246–62.

—— —— Ewing, S., Carette, M. J., Metcalfe, K., Donnai, D., Read, A. P., Tassabehji,M. (2002), ‘Using case study comparisons to explore genotype/phenotype correla-tions in Williams Syndrome’. (submitted).

—— Tyler, L. K., Voice, K., Sims, K., Udwin, O., Davies, M., & Howlin, P. (1998),‘Linguistic Dissociations in Williams Syndrome: Evaluating Receptive Syntax inon-line and off-line tasks’, Neuropsychologia, 36/4: 342–51.

Laing, E., Hulme, C., & Karmiloff-Smith, A. (2001), ‘Beyond reading scores: Theprocess of learning to read in Williams syndrome’, Journal of Child Psychologyand Psychiatry, 42/6: 729–39.

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elementary, my dear watson, the clue is in the genesor is it?

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